Calcium Release-activated calcium (CRAC) channels are a sub family of SOCs that are present on the plasma membrane and mediate several functions ranging from secretion to gene expression and cell growth. Additionally, they form a network essential for the activation of immune cells that establish the adaptive immune response. These channels open in response to depletion of endoplasmic calcium stores and are present majorly in non-excitable cells such as T-lymphocytes and mast cells. The activation of CRAC channels in the plasma membranes of these cells results in alteration in NFAT-dependent expression of several cytokines including interleukin-2. Although Interleukin-2 (IL-2) inhibitors acting through calcineurin pathway serve as potential immunosuppressive agents, they are limited by nephrotoxicity and neurotoxicity. Because localization of these channels is restricted to non-excitable cells, inhibition of calcium influx by altering CRAC channel activity is expected to be an effective and safe strategy for the treatment of autoimmune and inflammatory diseases. Furthermore, studies in subjects with non-functional CRAC channels suggest that inhibition of this target is both safe and efficacious.

Several human diseases have been linked to abnormal CRAC channel activity, including respiratory disorders, severe combined immunodeficiency (SCID) disorders, rheumatoid arthritis, inflammatory bowel disease, thrombosis and breast cancer. To date, there are few small molecules in clinical development for the treatment of rheumatoid arthritis; therefore CRAC channel inhibitors provide an exciting alternative at countering these diseases. Pharmacological suppression of CRAC channel activity reduced pro-inflammatory cytokine expression in laminar propria mononuclear cells isolated from patients with inflammatory bowel disease thereby implicating a potential therapeutic role. The contribution of CRAC channels to asthma stems from several studies in pre-clinical models wherein these channels have been shown to regulate mast cell activation and subsequent downstream effects. Drugs targeting CRAC channels could therefore be of immense clinical benefit

References:

Parekh, A. B. (2010) Nat. Rev. Drug Discov. 9:399-410

Feske, S. (2011) Ann. N. Y. Acad. Sci. 1238: 74-90

Current Status : Late Pre-Clinical

PI3K δ/γ Inhibitors

Phosphoinositide-3 kinases (PI3K) are critical components of the immune-cell signalling network and generate phosphatidylinositol (3,4,5) triphosphate that act as second messengers regulating downstream processes. While α and α isoforms are ubiquitous in their distribution, expression of δ and γ is restricted to hematopoetic cells and have been studies extensively in the context of immune-inflammatory disorders. While PI3K γ plays a non-redundant role in neutrophil, macrophage, and T-cell chemotaxis, maturation and migration of B-cells is exclusively governed by PI3K δ. Given their expression profiles, anomalies of PI3K δ / γ regulation are implicated in diseases arising due to abnormal immune cell expansion and/or function including immune-inflammatory conditions such as rheumatoid arthritis, fibrosis, COPD, and asthma.